STAT3 (Signal Transducers and Activators of Transcription 3), a member of the Janus kinase (JAK)/STAT signaling pathway, is a central transcription factor activated by phosphorylation of a conserved tyrosine residue (Tyr705) in response to extracellular cytokines and growth factors. Once activated, STAT3 dimerizes and translocates into nucleus to induce transcription of downstream target genes. Overexpression and/or constitutive activation of STAT3 has been detected in a number of human malignancies including lung and breast cancers. Subcutaneous injection of cells harboring constitutively-activated STAT3 (STAT3c) resulted in tumor formation. STAT3c overexpression in mouse alveolar type II epithelial cells led to lung inflammation and consequently spontaneous lung bronchoalveolar adenocarcinoma. Furthermore, inhibiting STAT3 expression using antisense oligonucleotides significantly impaired the growth of human and mouse nucleophosmin-anaplastic lymphoma kinase tumors in xenograft models. Thus, STAT3 is an attractive target for anticancer drug discovery.
Various inhibitors of STAT3 have been identified in the past, including peptidomimetics and small molecule compounds designed from the peptidomimetics or via high-throughput and virtual screening. Some of these inhibitors suppressed tumor growth in vivo, but none have moved into clinical testing. The common feature of all these inhibitors is that they are designed to inhibit the binding of SH2 domain to pTyr705 residue for activation or to inhibit phosphorylation of Tyr705. This approach is problematic because unphosphorylated STAT3 can bind to DNA and may still be functional. Thus, disrupting the interactions between SH2 domain and pTyr705 of STAT3 or STAT3 activation alone may not completely inhibit STAT3.
Interestingly, targeting the DNA-binding domain (DBD) of STAT3 has not been in the main stream of research, possibly because DBS is generally considered “undruggable” with flat and similar surface areas that may not allow appropriate and selective binding by small molecules. Nevertheless, a decoy oligonucleotide targeting the DBD of STAT3 is currently in clinical testing for human head and neck cancers.
Thus, inhibiting STAT3 promises an attracting strategy for treatment of advanced and metastatic cancers.